Method for preparing enantiomerically pure 4-pyrrolidino phenylbenzyl ether derivatives

ABSTRACT

The invention relates to a method for preparing enantiomerically pure 4-pyrrolidinophenylbenzyl ether derivatives of formula I: 
                         
wherein R 1 , R 21 , R 22 , R 23 , R 24  and n are as defined in the description and claims and to intermediates useful in the method of the invention as well as salts thereof.

PRIORITY TO RELATED APPLICATIONS

This application is a division of U.S. application Ser. No. 11/370,668,filed Mar. 8, 2006, now pending; which claims the benefit of EuropeanApplication No. 05102030.3, filed Mar. 15, 2005. The entire contents ofthe above-identified applications are hereby incorporated by reference.

BACKGROUND OF THE INVENTION

Monoamine oxidase (MAO, EC 1.4.3.4) is a flavin-containing enzymeresponsible for the oxidative deamination of endogenous monoamineneurotransmitters such as dopamine, serotonin, adrenaline, ornoradrenaline, and trace amines, e.g. phenylethyl-amine, as well as anumber of amine xenobiotics. The enzyme exists in two forms, MAO-A andMAO-B, encoded by different genes [Bach et al., Proc. Natl. Acad. Sci.USA 85:4934-4938 (1988)] and differing in tissue distribution, structureand substrate specificity. MAO-A has higher affinity for serotonin,octopamine, adrenaline, and noradrenaline; whereas the naturalsubstrates for MAO-B are phenylethylamine and tyramine. Dopamine isthought to be oxidised by both isoforms. MAO-B is widely distributed inseveral organs including brain [Cesura and Pletscher, Prog. DrugResearch 38:171-297 (1992)]. Brain MAO-B activity appears to increasewith age. This increase has been attributed to the gliosis associatedwith aging [Fowler et al., J. Neural. Transm. 49:1-20 (1980)].Additionally, MAO-B activity is significantly higher in the brains ofpatients with Alzheimer's disease [Dostert et al., Biochem. Pharmacol.38:555-561 (1989)] and it has been found to be highly expressed inastrocytes around senile plaques [Saura et al., Neuroscience 70:755-774(1994)]. In this context, since oxidative deamination of primarymonoamines by MAO produces NH₃, aldehydes and H₂O₂, agents withestablished or potential toxicity, it is suggested that there is arationale for the use of selective MAO-B inhibitors for the treatment ofdementia and Parkinson's disease. Inhibition of MAO-B causes a reductionin the enzymatic inactivation of dopamine and thus prolongation of theavailability of the neurotransmitter in dopaminergic neurons. Thedegeneration processes associated with age and Alzheimer's andParkinson's diseases may also be attributed to oxidative stress due toincreased MAO activity and consequent increased formation of H₂O₂ byMAO-B. Therefore, MAO-B inhibitors may act by both reducing theformation of oxygen radicals and elevating the levels of monoamines inthe brain.

Given the implication of MAO-B in the neurological disorders mentionedabove, there is considerable interest to obtain potent and selectiveinhibitors that would permit control over this enzymatic activity. Thepharmacology of some known MAO-B inhibitors is for example discussed byBentue-Ferrer et al. [CNS Drugs 6:217-236 (1996)]. Whereas a majorlimitation of irreversible and non-selective MAO inhibitor activity isthe need to observe dietary precautions due to the risk of inducing ahypertensive crisis when dietary tyramine is ingested, as well as thepotential for interactions with other medications [Gardner et al., J.Clin. Psychiatry 57:99-104 (1996)], these adverse events are of lessconcern with reversible and selective MAO inhibitors, in particular ofMAO-B. Thus, there is a need for MAO-B inhibitors with a highselectivity and without the adverse side-effects typical of irreversibleMAO inhibitors with low selectivity for the enzyme.

Compounds of Formula (I)

whereinR¹ is halogen, halogen —(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy, or halogen—(C₁-C₆)-alkoxy,R²¹, R²², R²³, and R²⁴ are each independently selected from hydrogen andhalogen; andn is 0, 1, 2 or 3are selective monoamine oxidase B inhibitors.

The preparation of MAO-B inhibitors of formula (I) has been disclosed incommonly owned patent application WO 2004/026825. However, that patentapplication does not disclose the process of the instant invention.

SUMMARY OF THE INVENTION

The invention provides a method for preparing enantiomerically pure4-pyrrolidinophenylbenzyl ether derivatives. This method producescompounds of formula (I) with high yields and purity. The invention alsoprovides intermediates that are useful in the method of the inventionand salts thereof.

More particularly, the present invention provides a method for preparingenantiomerically pure 4-pyrrolidino phenylbenzyl ether derivatives ofthe formula (I):

said method comprisinga) resolving a racemate of formula (II):

with a resolving agent to obtain the (S)-enantiomer thereof of formula(S)-(II):

b) converting the enantiomer of formula (S)-(II) into the correspondingprimary amide of formula (III):

c) either directly reacting the compound of formula (III) with acompound of formula (IV):ArI(OCOR)₂  (IV)in the presence of at least acetic acid and/or acetic anhydride toobtain the compound of formula (I);d) or reacting the compound of formula (III) with the compound offormula (IV) to obtain a compound of formula (V):

and then reacting the compound of formula (V) with an acetylating agentto obtain the compound of formula (I);wherein in the above formulae,Ar is an aryl group, optionally substituted by one or more substituentselected from the group consisting of halogen, nitro, cyano and(C₁-C₆)-alkyl;R is (C₁-C₆)-alkyl optionally substituted by one or more halogen atoms;R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy;R²¹, R²², R²³ and R²⁴ are each independently selected from the groupconsisting of hydrogen and halogen; andn is 0, 1, 2 or 3.

DETAILED DESCRIPTION OF THE INVENTION

The following definitions of general terms used herein applyirrespective of whether the terms in question appear alone or incombination. It must be noted that, as used in the specification and theappended claims, the singular forms “a”, “an,” and “the” include pluralforms unless the context clearly dictates otherwise.

In the structural formulae presented herein a wedged bond (

) denotes that the substituent is above the plane of the paper.

In the structural formulae presented herein a dotted bond (

) denotes that the substituent is below the plane of the paper.

The term “lower alkyl or (C₁-C₆)-alkyl” used in the present applicationdenotes indifferently straight-chain or branched saturated hydrocarbonresidues with 1 to 6 carbon atoms, such as methyl, ethyl, n-propyl,i-propyl, n-butyl, sec-butyl, t-butyl, and the like, preferably with 1to 3 carbon atoms. Accordingly, the term “(C₁-C₃)-alkyl” means astraight-chain or branched saturated hydrocarbon residue with 1 to 3carbon atoms.

“(C₁-C₆)-Alkoxy” means the residue —O—R, wherein R is a (C₁-C₆)-alkylresidue as defined herein. Examples of alkoxy radicals include, but arenot limited to, methoxy, ethoxy, isopropoxy, and the like.

The term “halogen” denotes fluorine, chlorine, bromine and iodine.

“Halogen-(C₁-C₆)-alkyl” or “halogen-(C₁-C₆)-alkoxy” means the loweralkyl residue or lower alkoxy residue, respectively, as defined hereinsubstituted in any position with one or more halogen atoms as definedherein. Examples of halogenalkyl residues include, but are not limitedto, 1,2-difluoropropyl, 1,2-dichloropropyl, trifluoromethyl,2,2,2-trifluoroethyl, 2,2,2-trichloroethyl, and 1,1,1-trifluoropropyl,and the like. “Halogenalkoxy” includes trifluoromethyloxy.

“Pharmaceutically acceptable salts” of a compound means salts that arepharmaceutically acceptable, which are generally safe, non-toxic, andneither biologically nor otherwise undesirable, and that possess thedesired pharmacological activity of the parent compound. These salts arederived from an inorganic or organic acid or base. If possible,compounds of formula (I) can be converted into pharmaceuticallyacceptable salts. It should be understood that pharmaceuticallyacceptable salts are included in the present invention.

The expression “enantiomerically pure” denotes an enantomeric ratio ofthe desired enantiomer of at least 95:5, preferably at least 98:2 andstill more preferably at least 99.9:0.1 with respect to the undesiredenantiomer. The enantiomeric ratio can be determined by HPLC on a chiralcolumn.

More particularly, the present invention provides a method for preparingenantiomerically pure 4-pyrrolidino phenylbenzyl ether derivatives ofthe formula (I):

said method comprisinga) resolving a racemate of formula (II):

with a resolving agent to obtain the (S)-enantiomer thereof of formula(S)-(II):

b) converting the enantiomer of formula (S)-(II) into the correspondingprimary amide of formula (III):

c) either directly reacting the compound of formula (III) with acompound of formula (IV):ArI(OCOR)₂  (IV)in the presence of at least acetic acid and/or acetic anhydride toobtain the compound of formula (I);d) or reacting the compound of formula (III) with the compound offormula (IV) to obtain a compound of formula (V):

and then reacting the compound of formula (V) with an acetylating agentto obtain the compound of formula (I);wherein in the above formulae,Ar is an aryl group optionally substituted by one or more substituentselected from the group consisting of halogen, nitro, cyano and(C₁-C₆)-alkyl;R is (C₁-C₆)-alkyl optionally substituted by one or more halogen atoms;R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy;R²¹, R²², R²³ and R²⁴ are each independently selected from the groupconsisting of hydrogen and halogen; andn is 0, 1, 2 or 3.

It is to be understood that in step a) any suitable resolving agentother than an enzyme can be used. In certain embodiments of theinvention the resolving agent used in step a) is selected from the groupconsisting of (R)-(−)-2-phenylglycinol=(R)-2-amino-2-phenyl-ethanol,(S)-(+)-2-phenylglycinol, cinchonidine, D-phenylalaminol,L-phenylalaminol, (+)-phenylethylamine, (1S,2S)-(+)-thiomicamine,(1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,(1S,2R)-(−)-cis-1-amino-2-indanol, L-phenylephrine,(1S,2R)-(+)-N-methylephedrine, L-prolinol, (R)-(−)-2-amino-1-butanol and(R)-(+)-1-(-naphthyl)-ethylamine. The preferred resolving agent is(R)-phenylglycinol.

In particular, the compound of formula (S)-(II) can be obtained bydirectly preparing a salt of the (S)-(II) compound with a resolvingagent capable of forming a salt of the (S)-(II) compound with theracemate (II).

Alternatively, the compound of formula (S)-(II) can be obtainedindirectly by preparing a salt of the (R)-(II) compound with a resolvingagent capable of forming a salt of the (R)-(II) compound with theracemate (II) and then removing the (R)-(II) compound from the racemateto keep the (S)-(II) compound in the reacting mixture.

Preferred resolving agents capable of forming a salt of the (S)-(II)compound with the racemate (II) are (R)-(−)-2-phenylglycinol,cinchonidine, D-phenylalaminol, (+)-phenylethylamine,(1S,2R)-(−)-cis-1-amino-2-indanol, and L-phenylephrine, the mostpreferred resolving agent being (R)-(−)-2-phenylglycinol.

Preferred resolving agents capable of forming a salt of the (R)-(II)compound with the racemate (II) are (S)-(+)-2-phenylglycinol,(1S,2S)-(+)-thiomicamine, (1S,2S)-(+)-2-amino-1-phenyl-1,3-propanediol,(1S,2R)-(+)-N-methylephedrine, L-prolinol, (R)-(−)-2-amino-1-butanol and(R)-(+)-1-(-naphthyl)-ethylamine. The preferred resolving agent is(S)-(+)-2-phenylglycinol.

In certain embodiments of the invention, the reaction in step a) isperformed without a solvent. In certain other embodiments of theinvention a solvent can be used in step a). This solvent can be selectedfrom the group consisting of acetone, isopropanol, acetonitrile,tetrahydrofuran, 2-butanone, isopropanol, EtOH and their mixtures withwater. The preferred solvent is a mixture of acetonitrile and water.

In one embodiment, step a) of the method according to invention forresolving a racemate of formula (II) to directly obtain an enantiomer offormula (S)-(II) suitably comprises:

a1) preparing a reaction mixture in a solvent comprising the racemate(II) and a resolving agent capable of forming a salt of the (S)-(II)compound with the racemate (II) to obtain a salt of the compound(S)-(II);

a2) isolating the salt of the compound (S)-(II) from the reactionmixture and liberating said compound (S)-(II) from its salt;

a3) isolating the compound (R)-(II) remaining in the reaction mixture ofstep a1);

a4) racemizing the isolated compound (R)-(II) to obtain a recycledracemate;

a5) repeating steps a1) to a4) using the recycled racemate in place ofthe original racemate.

In another embodiment, step a) of the method according to invention forresolving a racemate of formula (II) to indirectly obtain the enantiomerthereof of formula (S)-(II) by removing the (R)-(II) enantiomer suitablycomprises:

a1′) preparing a reaction mixture in a solvent comprising the racemate(II) and a resolving agent capable of forming a salt of the (R)-(II)compound with the racemate (II) to obtain a salt of the compound(R)-(II);

a2′) isolating the salt of the compound (R)-(II) from the reactionmixture and liberating said compound (R)-(II) from its salt;

a3′) isolating the compound (S)-(II) remaining in the reaction mixtureof step a1′);

a4′) racemizing the isolated compound (R)-(II) to obtain a recycledracemate;

a5′) repeating steps a1′) to a4′) using the recycled racemate in placeof the original racemate.

Steps a2) to a4) and a2′) to a4′) can be performed using conventionalmethods and equipment, for example extraction, crystallization,filtration, etc. Steps a1) to a4) and a1′) to a4′) can be repeated usingrecycled racemate as many times as necessary to obtain all of thecompound (S)-(II) possible from the original reaction mixture.

In certain embodiments of the invention the conversion of the enantiomerof formula (S)-(II) into the corresponding primary amide of formula(III) according to step b) can be performed by using1,1′-carbonyldiimidazole and a source of ammonia, e.g. aqueous ammoniaor ammonium acetate.

In certain other embodiments of the invention the conversion of theenantiomer of formula (S)-(II) into the corresponding primary amide offormula (III) according to step b) can be performed by usingN-methylmorpholine, ethyl chloroformate and a source of ammonia, e.g.gaseous ammonia.

Step b) can be performed in the presence or in the absence of a solvent.A solvent can also be used in step b), for example tetrahydrofuran(THF). The resulting compound of formula (III) can then be isolated andpurified using conventional methods and equipment such as concentrationin vacuo, dilution, extraction, precipitation, filtration, etc.

In Step c) preferred compounds of formula (IV):ArI(OCOR)₂  (IV)are those compounds wherein Ar is unsubstituted phenyl and R is Me, CF₃or Cl₃ or CCl₃ for example (diacetoxyiodo)benzene.

Steps c) and d) according to the method of the invention representalternative routes to obtain the compound of formula (I) starting fromthe compound of formula (III).

Step c) is a one-step alternative comprising reacting the compound offormula (III) with the compound of formula (IV) in the presence of atleast acetic acid and/or acetic anhydride, which directly leads to thecompound of formula (I).

In one embodiment of step c), the reaction of the compound of formula(III) with a compound of formula (IV) is performed in the presence of atleast acetic acid. In another embodiment of step c), the reaction of thecompound of formula (III) with the compound of formula (IV) is performedin the presence of at least acetic anhydride. In still anotherembodiment of step c), the reaction of the compound of formula (III)with the compound of formula (IV) is performed in the presence of atleast acetic acid and acetic anhydride.

The compound of formula (I) can then be isolated and purified usingconventional methods and equipment, for example using conventionalextraction, filtration, distillation, crystallization, etc.

Step d) is a two-step alternative comprising the reaction of thecompound of formula (III) with a compound of formula (IV):ArI(OCOR)₂  (IV)wherein Ar and R are as defined above,to obtain a compound of formula (V):

and then reacting the compound of formula (V) with an acetylating agentto obtain the compound of formula (I).

In certain embodiments of step d) according to the invention, thecompound of formula (IV) is (diacetoxyiodo)benzene: (PhI(OAc)₂).

In certain embodiments of step d) according to the invention, theacetylating agent can be acetic anhydride (Ac₂O) or acetyl chloride.

In certain embodiments of the invention step d) can be performed in asuitable solvent, e.g. in tetrahydrofuran (THF) with water, e.g. in aratio of about 1:1. In certain other embodiments of the invention stepd) can be performed in the absence of a solvent.

The compound of formula (I) can then be isolated and purified usingconventional methods and equipment.

The racemate of formula (II) can be prepared as described in WO2004/026825, the content of which is incorporated herein by reference.

The invention hence encompasses the following novel intermediatesinvolved in the method of the invention:

the salts of the compound of formula (S)-(II) with a resolving agentselected from the group consisting of (R)-(−)-2-phenylglycinol,cinchonidine, D-phenylalaminol, (+)-phenylethylamine,(1S,2R)-(−)-cis-1-amino-2-indanol, and L-phenylephrine, the mostpreferred resolving agent being (R)-(−)-2-phenylglycinol;

and the intermediate of formula (III):

wherein R¹, R²¹, R²², R²³, R²⁴ and n are as defined hereinabove.

Preferred compound of formula (S)-(II) and salts thereof with the aboverecited resolving agents are those compounds wherein:

R¹ is 3-fluoro;

R²¹, R²², R²³ and R²⁴ are hydrogen; and

n is 1.

Preferred intermediate of formula (III) are those compounds wherein:

R¹ is 3-fluoro;

R²¹, R²², R²³ and R²⁴ are hydrogen; and

n is 1.

In a certain embodiment of the method according to the invention, theracemate (II) is(RS)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid, (S)-(II) is(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid, the compound of formula (III) is(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid amide using 1,1′-carbonyldiimidazole, the compound of formula (V)is (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one, andthe compound of formula (I) is(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide.

The compounds of formula (I) are, as already mentioned hereinabove,monoamine oxidase B inhibitors and can be used for the treatment ofdiseases in which MAO-B inhibitors might be beneficial. These includeacute and chronic neurological disorders, cognitive disorders and memorydeficits. Treatable neurological disorders are for instance traumatic orchronic degenerative processes of the nervous system, such asAlzheimer's disease, other types of dementia, minimal cognitiveimpairment or Parkinson's disease. Other indications include psychiatricdiseases such as depression, anxiety, panic attack, social phobia,schizophrenia, eating and metabolic disorders such as obesity, as wellas the prevention and treatment of withdrawal syndromes induced by abuseof alcohol, nicotine and other addictive drugs. Other treatableindications may be peripheral neuropathy caused by cancer chemotherapy(WO 97/33,572), reward deficiency syndrome (WO 01/34,172), or thetreatment of multiple sclerosis (WO 96/40,095), and otherneuroinflammatory diseases.

The compounds of formula (I) are especially useful for the treatment ofAlzheimer's disease and senile dementia.

The pharmacological activity of the compounds was tested using thefollowing method: The cDNAs encoding human MAO-A and MAO-B weretransiently transfected into EBNA cells using the procedure described bySchlaeger and Christensen [Cytotechnology 15:1-13 (1998)]. Aftertransfection, cells were homogenised by means of a Polytron homogenizerin 20 mM Tris HCl buffer, pH 8.0, containing 0.5 mM EGTA and 0.5 mMphenylmethanesulfonyl fluoride. Cell membranes were obtained bycentrifugation at 45,000×g and, after two rinsing steps with 20 mM TrisHCl buffer, pH 8.0, containing 0.5 mM EGTA, membranes were eventuallyre-suspended in the above buffer and aliquots stored at −80° C. untiluse.

MAO-A and MAO-B enzymatic activity was assayed in 96-well-plates using aspectrophotometric assay adapted from the method described by Zhou andPanchuk-Voloshina [Analytical Biochemistry 253:169-174 (1997)]. Briefly,membrane aliquots were incubated in 0.1 M potassium phosphate buffer, pH7.4, for 30 min at 37° C. containing different concentrations of thecompounds. After this period, the enzymatic reaction was started by theaddition of the MAO substrate tyramine together with 1 U/ml horse-radishperoxidase (Roche Biochemicals) and 80 μMN-acetyl-3,7-dihydroxyphenoxazine (Amplex Red, Molecular Probes). Thesamples were further incubated for 30 min at 37° C. in a final volume of200 μl and absorbance was then determined at a wavelength of 570 nmusing a SpectraMax plate reader (Molecular Devices). Background(non-specific) absorbance was determined in the presence of 10 μMclorgyline for MAO-A or 10 μM L-deprenyl for MAO-B. IC₅₀ values weredetermined from inhibition curves obtained, using nine inhibitorconcentrations in duplicate, by fitting data to a four parameterlogistic equation using a computer program.

The compounds of the present invention are specific MAO-B inhibitors.The IC₅₀ values of preferred compounds of formula (I) as measured in theassay described above are in the range of 1 μM or less, typically 0.1 μMor less, and ideally 0.02 μM or less.

The present invention also provides pharmaceutical compositionscontaining compounds of the invention and a pharmaceutically acceptablecarrier. Such pharmaceutical compositions can be in the form of tablets,coated tablets, dragées, hard and soft gelatin capsules, solutions,emulsions or suspensions. The pharmaceutical compositions also can be inthe form of suppositories or injectable solutions.

The pharmaceutical compositions of the invention, in addition to one ormore compound of the invention, contain a pharmaceutically acceptablecarrier. Suitable pharmaceutically acceptable carriers includepharmaceutically inert inorganic or organic carriers. Lactose, cornstarch or derivatives thereof, talc, stearic acid or its salts and thelike can be used, for example, as such carriers for tablets, coatedtablets, dragées and hard gelatine capsules. Suitable carriers for softgelatine capsules are, for example, vegetable oils, waxes, fats,semi-solid and liquid polyols and the like; depending on the nature ofthe active substance no carriers are, however, usually required in thecase of soft gelatine capsules. Suitable carriers for the production ofsolutions and syrups are, for example, water, polyols, sucrose, invertsugar, glucose and the like. Adjuvants, such as alcohols, polyols,glycerol, vegetable oils and the like, can be used for aqueous injectionsolutions of water-soluble salts of compounds of formula I, but as arule are not necessary.

Suitable carriers for suppositories are, for example, natural orhardened oils, waxes, fats, semi-liquid or liquid polyols and the like.

In addition, the pharmaceutical compositions can contain preservatives,solubilizers, stabilizers, wetting agents, emulsifiers, sweeteners,colorants, flavorants, salts for varying the osmotic pressure, buffers,masking agents or antioxidants. They may also contain othertherapeutically valuable substances.

Compounds of the present invention can be formulated into suchpharmaceutical compositions, for example, by bringing one or morecompounds of the invention, and if desired, one or more othertherapeutically valuable substance into a galenical dosage form togetherwith one or more therapeutically inert carrier.

The dosage at which compounds of the invention can be administered canvary within wide limits and will, of course, be fitted to the individualrequirements in each particular case. In general, the effective dosagefor oral or parenteral administration is between 0.01-20 mg/kg/day, witha dosage of 0.1-10 mg/kg/day being preferred for all of the indicationsdescribed. The daily dosage for an adult human being weighing 70 kgaccordingly lies between 0.7-1400 mg per day, preferably between 7 and700 mg per day.

The following examples are provided for illustration of the invention.They should not be considered as limiting the scope of the invention,but merely as being representative thereof. The abbreviation “RT” means“room temperature”.

Example 1 Preparation ofrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicAcid (Compound of Formula (II))

4-(3-Fluoro-benzyloxy)-phenylamine (31.2 g, 144 mmol) was dissolved intoluene (208 mL) and acetic acid (52 mL). Itaconic acid (18.96 g, 144mmol) was added to the stirred mixture. The mixture was heated to reflux(101° C.) and kept at this temperature for 3 h. On cooling, the productstarted to crystallize. At 10° C., heptane (125 mL) was added to thesuspension which was stirred 1 h at 0° C. and filtered. The crystalswere washed with toluene/heptane 1:1 and with heptane and dried in vacuoto afford the crude product (43.2 g). The crude product was purified bytreatment with hot isopropyl acetate to giverac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (40.5 g, 86%; HPLC: 99.2% area), m.p. 148-149° C. (uncorr.).

Example 2 Preparation of(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicAcid [(S)-(II)] Including Recovery of the Undesired Enriched (R)-(II)and its Racemization (Step a) According to the Invention) a) Preparationof the Salt of the Compound of Formula (S)-(II) with(R)-(−)-2-phenylglycinol

rac-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (15.0 g, 45.6 mmol) was dissolved in acetonitrile/water 95:5 (150mL) at 75° C. At this temperature, a solution of(R)-(−)-2-phenylglycinol (6.25 g, 45.6 mmol) in acetonitrile/water 95:5(10 mL) was added. The current for the heating bath was turned off andcrystallization was initiated by addition of some seeding crystals.Stirring was continued for 3 h while the suspension slowly cooled toroom temperature. The crystals were collected by filtration, washed withwarm (40° C.) acetonitrile and dried in vacuo to afford the title salt(9.9 g, 47%) in >99.9:0.1 dr as determined by HPLC, [a]_(D)−4.7 (c=1,MeOH).

b) Liberation of the Compound of Formula (S)-(II) from the Salt

In a separation funnel, the main portion of the above salt (8.95 g, 19.2mmol) was added to ethyl acetate (140 mL). Under occasional shaking, icewater (˜100 mL) and 2 N sulfuric acid (˜25 mL) was added in severalportions until pH 2 was reached. The aqueous phase was separated andextracted with ethyl acetate (140 mL). The organic layers were washedwith diluted brine, combined, dried over sodium sulfate and concentratedto a volume of ˜40 mL. Heptane (30 mL) was added to the suspension whichwas stirred 2 h at 0° C. The crystals were collected by filtration,washed with heptane and dried in vacuo. Purification of the product bytreatment with hot isopropyl acetate afforded the(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (6.37 g, 47% based on racemic acid) as white crystals, m.p. 157° C.According to HPLC determination, the purity was 100% (area) and theenantiomeric ratio>99.9:0.1.

c) Isolation of the Enriched (R)-(II) Compound

The mother liquor obtained from the isolation of the phenylglycinol saltof the (S)-(II) compound as described in section a) was concentrated togive a crude phenylglycinol salt (11.4 g) containing the enriched(R)-(II) compound. Together with ethyl acetate (140 mL) this materialwas added to the acidic aqueous phase remaining from the liberation ofthe (S)-(II) compound described in section b). The aqueous phaseresulting after dissolution of the salt was still acidic. After thoroughmixing the aqueous phase was separated and extracted with anotherportion of ethyl acetate (140 mL). The organic phases were washed withhalf-concentrated aqueous sodium chloride, combined, dried over sodiumsulfate (75 g) and concentrated to a volume of ˜40 mL. Heptane (30 mL)was added to the suspension which was stirred 2 h at 0° C. The crystalswere collected by filtration, washed with heptane and dried in vacuo toafford enriched(R)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (7.4 g, 49% based on racemic acid) as a white solid. The purity ofthe material by HPLC was 98.8% (area) and the enantiomeric ratio (R):(S)was determined as 91.5:8.5.

d) One-Pot Racemization of the Enriched (R)-(II) Compound

The enriched (R)-(II) compound (7.4 g) obtained as described in sectionc) was suspended in methanol (50 mL). To the suspension conc. sulfuricacid (0.11 g) and 2,2-dimethoxypropane was added. The mixture wasstirred 2 h at 80° C., until the enriched (R)-(II) compound wascompletely converted to the methyl ester as monitored by HPLC. Aftercooling to 5° C., a solution of 5.4 M sodium methoxide in methanol (2.91mL) diluted with methanol (4 mL) was added dropwise within 10 min. Theresulting reaction mixture was stirred 20 h at room temperature and thencooled to 10° C. At this temperature, 2 N NaOH (40 mL) was addeddropwise over 20 min. The reaction mixture was stirred at roomtemperature for 2 h and then concentrated in vacuo until the methanolwas removed. At 10° C., ice (25 g) was added to the residue followed bydropwise addition of 2 N sulfuric acid until pH 2 was reached. Theresulting suspension was stirred for an additional hour. The product wascollected by filtration, washed with water until neutral and dried invacuo at 40° C. to affordrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (7.1 g) as white powder. According to HPLC determination, thepurity was 97.3% (area) and the enantiomeric ratio 51.5:48.5.

Example 3 Resolution Using 0.7 eq (R)-Phenylglycinol (step a) Accordingto the Invention)

The salt of the (S)-(II) compound with (R)-(−)-2-phenylglycinol wasprepared in an analogous manner as described in Example 2 a) fromrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (5 g, 15.2 mmol) in acetonitrile/water 95:5 (50 mL) using asolution of only 1.46 g (R)-(−)-2-phenylglycinol (10.6 mmol, 0.7 eq) inacetonitrile/water 95:5 (3.3 mL). From the salt (3.2 g, 45% based onracemic acid) obtained in 99.7:0.3 diastereomeric ratio the (S)-(II)compound was liberated and purified in a similar manner as described inExample 2b) to afford(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (2.21 g, 44% based on racemic acid) in high purity (HPLC: 99.4%area) and with >99.9:0.1% er.

Example 4 Resolution Using 0.6 eq (R)-Phenylglycinol (Step a) Accordingto the Invention) a) Preparation of the Salt of the (S)-(II) Compoundwith (R)-(−)-2-Phenylglycinol

The salt of the (S)-(II) compound with (R)-(−)-2-phenylglycinol wasprepared in an analogous manner as described in Example 2 a) fromrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (60.00 g, 0.182 mol) in a mixture of acetonitrile (560 mL) andwater (34 mL) using a solution of only 15.00 g (R)-(−)-2-phenylglycinol(0.109 mol, 0.6 eq) in a mixture of acetonitrile (72 mL) and water (6mL) to yield 34.49 g (40% based on racemic acid) of the salt (dr99.7:0.3).

b) Liberation of the (S)-(II) Compound from the Salt

A suspension of the above salt (33.00 g, 70.74 mmol) in water (495 mL)was treated at 20-25° C. with 55.2 g sulfuric acid (10%) and theresulting suspension (pH 1.4-1.7) was stirred at 20-25° C. for 2-3 h.The crystals were collected by filtration, washed with water (2×125 mL)and dried in vacuo to afford(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (22.94 g, 40% based on racemic acid) as white crystals. Accordingto HPLC determination, the purity was 99.9% (m/m) and the enantiomericratio 99.7:0.3.

Example 5 Salt Formation Using 0.5 eq (R)-(−)-2-phenylglycinol (Step a)According to the Invention)

The salt of the (S)-(II) compound with (R)-(−)-2-phenylglycinol wasprepared in an analogous manner as described in Example 2 a) fromrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (10 g, 30.4 mmol) in acetonitrile/water 95:5 (100 mL) using asolution of only 2.083 g (R)-(−)-2-phenylglycinol (15.2 mmol, 0.5 eq) inacetonitrile/water 95:5 (6.7 mL). The salt (5.6 g, 39.5% based onracemic acid) was obtained in 99.8:0.2 diastereomeric ratio.

Example 6 Resolution in Isopropanol/Water (Step a) According to theInvention) a) Preparation of the Salt of the (S)-(II) Compound with(R)-(−)-2-Phenylglycinol

rac-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (5.0 g, 15.2 mmol) was dissolved in a mixture of isopropanol (47.5mL) and water (2.5 mL) at 75° C. At this temperature,(R)-(−)-2-phenylglycinol (2.08 g, 15.2 mmol) was added. The electricalpower for the heating bath was turned off and crystallization wasinitiated by addition of some seeding crystals. After 30 minutes theheating bath was removed and stirring was continued while the suspensionslowly cooled to room temperature. After 4 h, the crystals werecollected by filtration, washed with 95% aq. isopropanol and dried invacuo to afford crude salt (3.48 g) in 96.5:3.5 dr as determined byHPLC. The crude salt was treated in hot 95% aq. isopropanol to yield,after isolation, the title salt (3.24 g, 46%) in 97.9:2.1 dr.

b) Liberation of the (S)-(II) Compound from the Salt

The above salt (3.24 g, 6.94 mmol) was treated with ethyl acetate (50mL), ice (10 g) and 2 N sulfuric acid (4 mL). The aqueous phase wasseparated and extracted with ethyl acetate (20 mL). The organic layerswere washed with diluted brine, combined, dried over sodium sulfate (5g) and concentrated. The residue (2.21 g) was treated 20 h in refluxingisopropyl acetate (8 mL). After cooling, the crystals were collected byfiltration, washed with isopropyl acetate (2×3 mL) and dried in vacuo toafford(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (2.02 g, 40% based on racemic acid) in >99.9:0.1 er.

Examples 7-23 Resolution Experiments Using Alternative Resolving Agents(Comparative Examples) (Step a) According to the Invention)

Under stirringrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (100 mg) was dissolved in 95% aq. EtOH (1 mL) at 50° C. Theresolving agent (1 eq) was added and the resulting mixture was slowlycooled to room temperature. Stirring was continued overnight. Thecrystals formed were isolated by filtration. In cases where no crystalsappeared, diisopropyl ether (0.2 mL) was added and stirring wascontinued for some time before isolation of the crystals. From thecrystalline salt the free acid was isolated by extraction with ethylacetate after acidification using dilute sulfuric acid. The enantiomericratio (S):(R) was determined by HPLC on a chiral column and the resultsare shown in Table 1.

TABLE 1 Yield (%) of free Resolving agent acid (S):(R) Remarks(S)-(+)-2-Phenylglycinol 34 17:83 Cinchonidine 65 72:28 D-Phenylalaninol36 69:31 (R)-(+)-1-Phenylethylamine 28 68:32 (1S,2S)-(+)-Thiomicamine 4033:67 (1S,2S)-(+)-2-Amino-1- 62 34:66 phenyl-1,3-propanediolL-Phenylephrine 62 61:39 L-Prolinol 44 43:57 (R)-(−)-2-Amino-1-butanol30 45:55 (1S,2R)-(+)-N-Methyl- 27 47:53 ephedrine(+)-Dehydroabietylamine 10 48:52 Brucine No crystals formed CinchonineNo crystals formed D-(+)-Norephedrine No crystals formed Quinidine Nocrystals formed Quinine No crystals formed (−)-Sparteine No crystalsformed

Examples 24-33 Resolution Experiments in Various Solvents (IncludingComparative Examples) (Step a) According to the Invention)

Under stirringrac-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid was dissolved in hot solvent. The resolving agent (1 eq) was addedand the resulting mixture was slowly cooled to room temperature.Stirring was continued overnight. The crystals formed were isolated byfiltration. From a sample of the crystalline salt the free acid wasisolated by extraction with ethyl acetate after acidification usingdilute sulfuric acid. The enantiomeric ratio (S):(R) was determined byHPLC on a chiral column. The results are shown in Table 2.

TABLE 2 Results in various solvents (10 mL/1 g rac-acid) Amt. ofrac-acid Yield of Enantiomeric Resolving agent (eq) (g) Solvent salt (%)ratio (S):(R) (R)-(−)-2-Phenylglycinol (1.0) 1.0 95% aq. 50 93:7 acetone(R)-(−)-2-Phenylglycinol (1.0) 5.0 95% aq. 49 97:3 isopropanol(R)-(−)-2-Phenylglycinol (1.0) 1.0 95% aq. 39 99.1:0.9 acetonitrile(R)-(−)-2-Phenylglycinol (1.0) 1.0 95% aq. THF 27 95:5(R)-(−)-2-Phenylglycinol (0.55) 1.0 95% aq. 32 99.7:0.3 2-butanoneCinchonidine (1.0) 0.5 95% aq. 88  55:45 isopropanol D-Phenylalaninol(1.0) 0.5 95% aq. 66  54:46 isopropanol (1S,2S)-(+)-2-Amino-1-phenyl-0.5 95% aq. 80  45:55 1,3-propanediol (1.0) isopropanol(1S,2R)-(−)-cis-1-Amino-2- 0.2 95% aq. 60  54:46 indanol (1.0) EtOH(R)-(+)-1-(-Naphthyl)- 0.5 95% aq. 74  46:54 ethylamine (1.0)acetonitrile

Example 34 Preparation of(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicAcid Amide Using 1,1′-carbonyldiimidazole (Compound of Formula (III))(Step b) According to the Invention)

1,1′-carbonyldiimidazole (8.27 g, 51.0 mmol) was suspended and partlydissolved in tetrahydrofuran (110 mL) at 18° C.(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (14.0 g, 42.5 mmol; enantiomeric purity (S):(R)=99.5:0.5) was addedas a solid together with tetrahydrofuran (30 mL) used for rinsing. Theturbid solution, which turned into a white suspension after 15 min, wasstirred 1 h at 16-20° C. and then transferred into a stirred 25% aqueousammonia solution (7.95 mL) in tetrahydrofuran (80 mL). The last part ofthe white suspension was transferred with the aid of tetrahydrofuran (10mL) for rinsing. After stirring for 0.5 h the reaction mixture wasconcentrated in vacuo to a volume of ˜70 mL and diluted with water (300mL). Some ice was added to keep the temperature at 20-25° C. The whiteprecipitate was collected by filtration, washed withwater/tetrahydrofuran 80:20 and with heptane. Drying in vacuo at 20-45°C. afforded(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid amide (13.5 g, 96%) as a white solid. The purity of the material byHPLC was 96.9% (area) and the enantiomeric ratio (S):(R) was determinedas 99.7:0.3.

Example 35 Alternative Method for the Preparation of(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicAcid Amide (Compound of Formula (III)) (Step b) According to theInvention)

To (S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid (2.0 g, 6.07 mmol; enantiomeric purity (S):(R)>99.9:0.1) intetrahydrofuran (40 mL), N-methylmorpholine (676 mg, 6.68 mmol) wasadded at 0° C. After stirring for 20 min, a solution of ethylchloroformate (725 mg, 6.68 mmol) was added dropwise over 10 min, andstirring at 0° C. was continued for another 20 min. Ammonia (excess) wasthen bubbled for 15 min through the resulting suspension. The reactionmixture was warmed up to room temperature and stirred for 15 min. Water(50 mL) was added, and the tetrahydrofuran was evaporated in vacuo. Theproduct, which precipitated, was collected by filtration, washed withwater and tert-butyl methyl ether and dried at 45° C. in vacuo to afford(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid amide (1.75 g, 88%). The purity of the product by HPLC was 98.9%(area) and the enantiomeric ratio (S):(R) was determined as 99.8:0.2.

Example 36 Preparation of(S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (Compoundof Formula (V)) (Step d) According to the Invention)

(S)-1-[4-(3-Fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid amide (10.0 g, 30.5 mmol; enantiomeric purity (S):(R)=99.6:0.4,prepared using the method described in example 34) was suspended in amixture of tetrahydrofuran (80 mL) and water (80 mL). Under stirring(diacetoxyiodo)benzene (12.75 g, 39.6 mmol) was added in one portion at20° C. Stirring was continued and a water bath was used to keep thetemperature at 20° C. After a total reaction time of 3.5 h, less than0.5% starting material was left according to HPLC. To the reactionmixture ethyl acetate (100 mL) and aqueous 1 N methanesulfonic acid (50mL) were added. Tetrahydrofuran and ethyl acetate were removed byevaporation in vacuo and another portion of ethyl acetate (100 mL) wasadded to the residual mixture. The urea type by-product was removed byfiltration and washed with some ethyl acetate and water. The filtratewas transferred into a separatory funnel. The aqueous phase wasseparated and extracted with ethyl acetate. Each of the organic phaseswere washed with aqueous 0.1 N methanesulfonic acid (2×40 mL). Theaqueous phases were combined and the dissolved ethyl acetate was removedin vacuo. At 0° C. the pH was adjusted to 11 by addition of cold 40%aqueous NaOH and ice. The precipitate was collected by filtration,washed with water until the filtrate was neutral and dried in vacuo toafford (S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one(7.0 g, 76%), chemical purity as determined by HPLC (area): 98.8%. Theproduct was used for the following step without further purification.

Example 37 Preparation of(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide(Compound of Formula (I)) (Step d) According to the Invention)

In the reaction flask,(S)-4-amino-1-[4-(3-fluoro-benzyloxy)-phenyl]-pyrrolidin-2-one (7.0 g,23.3 mmol), prepared as described in the previous example, was chargedtogether with dichloromethane (70 mL). At 40° C., a solution of aceticanhydride (2.97 g, 29.1 mmol) in dichloromethane (10 mL) was addeddropwise under stirring over 30 min. After a reaction time of 1.5 h, nostarting material was left according to HPLC. Acetone (250 mL) was addedand the mixture was concentrated in vacuo to a volume of ˜50 mL. Theresidue was dissolved in acetone (250 mL) at 60° C. The warm solutionwas treated with charcoal, the resulting suspension filtered and thecharcoal washed with warm acetone. The filtrate was concentrated at 60°C. to a volume of ˜50 mL when the product started to crystallize. Atroom temperature, tert-butyl methyl ether (100 mL) was added and thesuspension was kept at this temperature overnight. The crystals werecollected by filtration, washed with tert-butyl methyl ether and driedin vacuo to afford(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide(7.0 g, 88%) as an off-white powder. The purity of the material by HPLCwas 99.4% (area) and the enantiomeric ratio (S):(R) was determinedas >99.9:0.1. The result of the elemental analyses (C,H,N,F,O)corresponded to the expected values.

Example 38 Preparation of(S)—N-{1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidin-3-yl}-acetamide(Compound of Formula (I)) (Step c) According to the Invention)

To a solution of(S)-1-[4-(3-fluoro-benzyloxy)-phenyl]-5-oxo-pyrrolidine-3-carboxylicacid amide (20.00 g, 60.91 mmol), (diacetoxyiodo)benzene (25.60 g, 79.48mmol) und sodium acetate (10.00 g, 12.19 mmol) in acetic acid (190 mL)was added acetic anhydride (20 mL) and the clear solution was heated to60° C. and stirred at this temperature for 16-20 h. The mixture wascooled to room temperature and 10% aqueous sodium sulfite solution (30mL) was added dropwise. Water (200 mL) was then added and the resultingsuspension was concentrated at 50-60° C. and 150-100 mbar. Anotherportion of water (200 mL) was added and the suspension was concentrated.This was repeated a third time with 100 mL water. To the suspension wasthen added water (300 mL) and dichloromethane (400 mL) and the layerswere separated. The aqueous phase was extracted with dichloromethane(200 mL). The combined organic layers were washed with water (3×200 mL).Dichloromethane was then distilled off and continuously replaced byethanol (500 mL) to a final volume of about 300 mL. This mixture wasthen heated to reflux temperature and the clear solution was treatedwith carbon (1.4 g). The black mixture was filtered and from thefiltrate the ethanol was distilled off and replaced by 2-butanone (260mL). The mixture was heated to 75-79° C. and stirred at this temperaturefor 1 h. Upon cooling and seeding the product started to crystallize at60° C. The mixture was cooled to 0-5° within 2-3 h and stirred at thistemperature for 1-2 h. The crystals were collected by filtration, washedwith 2-butanone (80 mL) and dried in vacuo to afford 15.79 g (75%) ofthe title compound as white crystals. According to HPLC determination,the purity was 99.0% (m/m) and the enantiomeric ratio 99.9:0.1.

1. A compound of formula (III):

wherein R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano, (C₁-C₆)-alkoxy orhalogen-(C₁-C₆)-alkoxy; R²¹, R²², R²³ and R²⁴ are each independentlyselected from the group consisting of hydrogen and halogen; and n is 0,1, 2 or
 3. 2. The compound of claim 1, wherein: R¹ is 3-fluoro; R²¹,R²², R²³ and R²⁴ are each hydrogen; and n is
 1. 3. A salt of thecompound of formula (S)-(II):

with a compound selected from the group consisting of(R)-(−)-2-phenylglycinol, cinchonidine, D-phenylalaminol,(+)-phenylethylamine, (1S,2R)-(−)-cis-1-amino-2-indanol, andL-phenylephrine; wherein R¹ is halogen, halogen-(C₁-C₆)-alkyl, cyano,(C₁-C₆)-alkoxy or halogen-(C₁-C₆)-alkoxy; R²¹, R²², R²³ and R²⁴ are eachindependently selected from the group consisting of hydrogen andhalogen; and n is 0, 1, 2 or
 3. 4. The salt of claim 3, of the compoundof formula (S)-(II) with (R)-(−)-2-phenylglycinol.
 5. The salt of claim3, wherein: R¹ is 3-fluoro; R²¹, R²², R²³ and R²⁴ are each hydrogen; andn is
 1. 6. The salt of claim 5, of the compound of formula (S)-(II) with(R)-(−)-2-phenylglycinol.